Low status, humiliation, dopamine and risk of schizophrenia.

The social defeat hypothesis of schizophrenia, which proposes that the chronic experience of outsider status or subordinate position leads to increased striatal dopamine activity and thereby to increased risk, has been criticized. The aims of this paper are to improve the definition of defeat and to integrate the social defeat hypothesis with the neurodevelopmental hypothesis. Marmot advanced the idea that low status is pathogenic in that it is associated with a lack of social participation and a lack of autonomy. Given the similarity with outsider status and subordinate position, we re-define social defeat as low status. From this new perspective it is also likely that pre-schizophrenic impairments (of neurodevelopmental origin or not) are pathogenic in that they contribute to low status. The effect of low status may be enhanced by repeated exposure to humiliation, but few studies have measured this variable. Since most individuals exposed to low status do not develop schizophrenia, we propose that this risk factor increases the risk of disorder in the presence of a poor homeostatic control of dopamine neurons in midbrain and dorsal striatum. This is consistent with studies of healthy subjects which report a negative association between low socio-economic status and dopamine D2/D3 receptor availability in the dorsal striatum. In this new version of the social defeat hypothesis we propose that the combination of low status, repeated humiliation and poor homeostatic control of dopamine neurons in midbrain and dorsal striatum leads to increased striatal dopamine activity and thereby to an increased risk of schizophrenia.

Annual Research Review: Stability of psychopathology: lessons learned from longitudinal population surveys.

BACKGROUND: Psychopathology has been long recognized as a fluctuating process with various expressions over time, which can only be properly understood if we follow individuals and their social context from childhood up until adulthood. Longitudinal population-based studies have yielded powerful data to analyze this process. However, the resulting publications have not been reflected upon with regard to (a) the homotypic and heterotypic stability of internalizing and externalizing problems and (b) how transactions between psychopathology and environmental factors shape its development. METHODS: In this narrative review, we primarily focused on population-based studies that followed cohorts repeatedly from an early age (<18 years) onwards, across multiple stages of development, using statistical methods that permit inferences about within-person bidirectional associations between internalizing and externalizing problems or psychopathology-environment transactions. RESULTS: There is robust evidence that mental health problems in childhood or adolescence predict psychiatric problems later in development. In terms of the broadband domains internalizing and externalizing problems, homotypic stability greatly exceeds heterotypic stability and transitions from purely internalizing to purely externalizing problems or vice versa are rare. Homotypic rank-order stabilities seem to increase over time. Findings regarding transactions with environmental factors are less robust, due to widely varying research topics and designs, and a scarcity of studies that separated between-person differences from within-person changes. In general, however, the literature shows little consistent evidence for substantial mutual prospective influences between psychopathology and environmental factors. CONCLUSIONS: Longitudinal surveys have strongly augmented insight into homotypic and heterotypic stability and change. Attempts to unravel the myriad of risk and protective factors that place individuals on particular pathways or deflect them from these pathways are still in a pioneering phase and have not yet generated robust findings. As a way forward, we propose to join forces and develop a common risk factor taxonomy.

Continuity of Psychopathology Throughout Adolescence and Young Adulthood.

OBJECTIVE: This study tested two opposing hypotheses on the continuity of psychopathology throughout adolescence and young adulthood; differentiation versus dynamic mutualism. Differentiation predicts that co-occurrence decreases, while dynamic mutualism predicts that co-occurrence increases due to causal interactions amongst mental health problems. METHOD: Using data from the Dutch TRacking Adolescents' Individual Lives Survey (n = 2228, 51% female), we studied the development of self-reported internalizing, externalizing, and attention problems at ages 11 to 26 across six waves. Random-intercept cross-lagged panel modeling was employed to distinguish within-person development from stable between-person processes. RESULTS: Large stable between-person associations indicated that adolescents with internalizing problems tended to have both externalizing and attention problems as well. On a within-person level, mental health problems showed partial stability and strong cross-sectional co-occurrence. Within-wave associations of internalizing with externalizing or attention problems decreased between age 11 and 16 years, after which they increased again. Little heterotypic continuity was found: age 11 externalizing predicted age 13 attention, which in turn predicted age 16 externalizing problems, and internalizing predicted externalizing problems across ages 22 to 26. Findings were similar for males and females. CONCLUSIONS: Our findings suggest co-occurrence decreases during early and middle adolescence, supporting differentiation. While co-occurrence increased again into young adulthood, this could not be labeled as dynamic mutualism because little evidence for heterotypic continuity was found in this phase of life. The strong stable links between internalizing, externalizing, and attention problems stress the importance of targeting these mental health problems and their shared risk factors together.

On Imbalance of Impulse Control and Sensation Seeking and Adolescent Risk: An Intra-individual Developmental Test of the Dual Systems and Maturational Imbalance Models.

Heterogeneity in development of imbalance between impulse control and sensation seeking has not been studied until now. The present study scrutinized this heterogeneity and the link between imbalance and adolescent risk. Seven-wave data of 7,558 youth (50.71% males; age range from 12/13 until 24/25) were used. Three developmental trajectories were identified. The first trajectory, "sensation seeking to balanced sensation seeking", included participants with a higher level of sensation seeking than impulse control across all ages. The second trajectory, "moderate dominant control", included participants showing moderate and increasing impulse control relative to sensation seeking across all ages. The third trajectory, "strong late dominant control", included participants showing the highest level of impulse control which was about as strong as sensation seeking from early to middle adolescence and became substantially stronger from late adolescence to early adulthood. Although the systematic increase of impulse control in all subgroups is in line with both models, neither of these combined trajectories of control and sensation seeking was predicted by the Dual Systems Model or the Maturational Imbalance Model. Consistent with both models the "sensation seeking to balanced sensation seeking" trajectory showed the highest level of substance use. It can be concluded that, even though both theories adequately predict the link between imbalance and risk, neither the Dual Systems Model nor the Maturational Imbalance Model correctly predict the heterogeneity in development of imbalance between impulse control and sensation seeking.

Debate: Giving prevention a chance to prove its worth in lowering common mental disorder prevalence: how long will it take?

Large increases in treatment of Common Mental Disorders (CMD) have failed to reduce population prevalence and global burden. Preventive strategies are needed to lower CMD prevalence and burden. Giving prevention a real chance to prove its promise will require: (a) full embedment in social institutions; (b) long-term structural funding; (c) targeting major CMD determinants early in life combining population-level and individual-level strategies; and, (d) integrated evaluation of short-term and long-term effects to guide implementation. Targeting life skills and resilience of children and parenting skills of their parents has the potential for long-term benefits for multiple outcomes including well-being, social, economic, and financial domains as well as mental health outcomes. However, the large investments may not occur without compelling proof of effectiveness, but evaluation of effectiveness cannot occur without long-term, structural investments. Overcoming this impasse requires a paradigm shift. Randomized controlled trials of initial efficacy need to be supplemented by evaluation strategies for long-term surveillance of community-based programs that guide implementation while assessing long-term effectiveness.

Les progrès dans la réalisation de la classification quantitative de la psychopathologie.

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level" dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity" by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach.

Effects of psychological treatment of mental health problems in pregnant women to protect their offspring: randomised controlled trial.

BACKGROUND: Perinatal depression and anxiety are associated with unfavourable child outcomes. AIMS: To assess among women with antenatal depression or anxiety the effectiveness of prenatally initiated cognitive-behavioural therapy (CBT) on mother and child compared with care as usual (CAU). Trial registration: Netherlands Trial Register number NTR2242. METHOD: Pregnant women (n = 282) who screened positive for symptoms of depression and/or anxiety were randomised to either CBT (n = 140) or CAU (n = 142). The primary outcome was child behavioural and emotional problems at age 18 months, assessed using the Child Behavior Checklist (CBCL). Secondary outcomes were maternal symptoms during and up to 18 months after pregnancy, neonatal outcomes, mother-infant bonding and child cognitive and motor development at age 18 months. RESULTS: In total, 94 (67%) women in the CBT group and 98 (69%) in the CAU group completed the study. The mean CBCL Total Problems score was non-significantly higher in the CBT group than in the CAU group (mean difference: 1.38 (95% CI -1.82 to 4.57); t = 0.85, P = 0.399). No effects on secondary outcomes were observed except for depression and anxiety, which were higher in the CBT group than in the CAU group at mid-pregnancy. A post hoc analysis of the 98 women with anxiety disorders showed lower infant gestational age at delivery in the CBT than in the CAU group. CONCLUSIONS: Prenatally initiated CBT did not improve maternal symptoms or child outcomes among non-help-seeking women with antenatal depression or anxiety. Our findings are not in line with present recommendations for universal screening and treatment for antenatal depression or anxiety, and future work may include the relevance of baseline help-seeking.

The antidepressant standoff: why it continues and how to resolve it.

BACKGROUND: Antidepressant medications (ADMs) are widely used and long-term use is increasing. Given this extensive use and recommendation of ADMs in guidelines, one would expect ADMs to be universally considered effective. Surprisingly, that is not the case; fierce debate on their benefits and harms continues. This editorial seeks to understand why the controversy continues and how consensus can be achieved. METHODS: 'Position' paper. Critical analysis and synthesis of relevant literature. RESULTS: Advocates point at ADMs impressive effect size (number needed to treat, NNT = 6-8) in acute phase treatment and continuation/maintenance ADM treatment prevention relapse/recurrence in acute phase ADM responders (NNT = 3-4). Critics point at the limited clinically significant surplus value of ADMs relative to placebo and argue that effectiveness is overstated. We identified multiple factors that fuel the controversy: certainty of evidence is low to moderate; modest efficacy on top of strong placebo effects allows critics to focus on small net efficacy and advocates on large gross efficacy; ADM withdrawal symptoms masquerade as relapse/recurrence; lack of association between ADM treatment and long-term outcome in observational databases. Similar problems affect psychological treatments as well, but less so. We recommend four approaches to resolve the controversy: (1) placebo-controlled trials with relevant long-term outcome assessments, (2) inventive analyses of observational databases, (3) patient cohort studies including effect moderators to improve personalized treatment, and (4) psychological treatments as universal first-line treatment step. CONCLUSIONS: Given the public health significance of depression and increased long-term ADM usage, new approaches are needed to resolve the controversy.

Where are the breaks in translation from theory to clinical practice (and back) in addressing depression? An empirical graph-theoretic approach.

BACKGROUND: Research in depression has progressed rapidly over the past four decades. Yet depression rates are not subsiding and treatment success is not improving. We examine the extent to which the gap between science and practice is associated with the level of integration in how depression is considered in research and stakeholder-relevant documents. METHODS: We used a network-science perspective to analyze similar uses of depression relevant terms in the Google News corpus (approximately 1 billion words) and the Web of Science database (120 000 documents). RESULTS: These analyses yielded consistent pictures of insular modules associated with: (1) patient/providers, (2) academics, and (3) industry. Within academia insular modules associated with psychology, general medical, and psychiatry/neuroscience/biology were also detected. CONCLUSIONS: These analyses suggest that the domain of depression is fragmented, and that advancements of relevance to one stakeholder group (academics, industry, or patients) may not translate to the others. We consider potential causes and associated responses to this fragmentation that could help to unify and advance translation from research on depression to the clinic, largely involving harmonizing employed language, bridging conceptual domains, and increasing communication across stakeholder groups.

Sequences of maladaptation: Preadolescent self-regulation, adolescent negative social interactions, and young adult psychopathology.

This study aims to test whether adolescent negative social interactions mediate the relation between early adolescent self-regulatory capacities and young adult psychopathology, using a fully prospective mediation model. Data were derived from the Tracking Adolescents' Individual Lives Survey, a large population cohort of Dutch adolescents (n = 962). At age 11, three indicators of self-regulation were assessed: low frustration, high effortful control, and high response inhibition. Negative social interactions between ages 11 and 22 were captured twice using the Event History Calendar. Psychopathology (i.e., internalizing and externalizing problems) was assessed at ages 11 and 22. Findings indicate that adolescents' frustration and effortful control but not response inhibition assessed at age 11 are related to both internalizing and externalizing problems at age 22, after controlling for psychopathology at age 11, sex, and socioeconomic status. These associations were partly (about 22%) mediated by the negative social interactions adolescents experienced. Effect sizes were all modest. This study shows that self-regulation is related to subsequent psychopathology in part through its effect on negative social interactions, providing evidence for sequences of self-regulatory capacities, life experiences, and developmental outcomes.

SNP-Based Heritability Estimates of Common and Specific Variance in Self- and Informant-Reported Neuroticism Scales.

OBJECTIVE: Our study aims to estimate the proportion of the phenotypic variance of Neuroticism and its facet scales that can be attributed to common single-nucleotide polymorphisms (SNPs) in two adult populations from Estonia (EGCUT; N = 3,292) and the Netherlands (Lifelines; N = 13,383). METHOD: Genomic-relatedness-matrix restricted maximum likelihood (GREML) using genome-wide complex trait analysis (GCTA) software was employed. To build upon previous research, we used self- and informant reports of the 30-facet NEO personality inventories and analyzed both the usual sum scores and the residual facet scores of Neuroticism. RESULTS: In the EGCUT cohort, the proportion of phenotypic variance explained by the additive effects of common genetic variants in self- and informant-reported Neuroticism domain scores was 15.2% (p = .070, SE = .11) and 6.2% (p = .293, SE = .12), respectively. The SNP-based heritability estimates at the level of Neuroticism facet scales differed greatly across cohorts and modes of measurement but were generally higher (a) for self- than for informant reports, and (b) for sum than for residual scores. CONCLUSIONS: Our findings indicate that a large proportion of the heritability of Neuroticism is not captured by additive genetic effects of common SNPs, with some evidence for Gene × Environment interaction across cohorts.

Discontinuation of antidepressant medication after mindfulness-based cognitive therapy for recurrent depression: randomised controlled non-inferiority trial.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) and maintenance antidepressant medication (mADM) both reduce the risk of relapse in recurrent depression, but their combination has not been studied. AIMS: To investigate whether MBCT with discontinuation of mADM is non-inferior to MBCT+mADM. METHOD: A multicentre randomised controlled non-inferiority trial (ClinicalTrials.gov:NCT00928980). Adults with recurrent depression in remission, using mADM for 6 months or longer (n= 249), were randomly allocated to either discontinue (n= 128) or continue (n= 121) mADM after MBCT. The primary outcome was depressive relapse/recurrence within 15 months. A confidence interval approach with a margin of 25% was used to test non-inferiority. Key secondary outcomes were time to relapse/recurrence and depression severity. RESULTS: The difference in relapse/recurrence rates exceeded the non-inferiority margin and time to relapse/recurrence was significantly shorter after discontinuation of mADM. There were only minor differences in depression severity. CONCLUSIONS: Our findings suggest an increased risk of relapse/recurrence in patients withdrawing from mADM after MBCT.

An approximate marginal logistic distribution for the analysis of longitudinal ordinal data.

Subject-specific and marginal models have been developed for the analysis of longitudinal ordinal data. Subject-specific models often lack a population-average interpretation of the model parameters due to the conditional formulation of random intercepts and slopes. Marginal models frequently lack an underlying distribution for ordinal data, in particular when generalized estimating equations are applied. To overcome these issues, latent variable models underneath the ordinal outcomes with a multivariate logistic distribution can be applied. In this article, we extend the work of O'Brien and Dunson (2004), who studied the multivariate t-distribution with marginal logistic distributions. We use maximum likelihood, instead of a Bayesian approach, and incorporated covariates in the correlation structure, in addition to the mean model. We compared our method with GEE and demonstrated that it performs better than GEE with respect to the fixed effect parameter estimation when the latent variables have an approximately elliptical distribution, and at least as good as GEE for other types of latent variable distributions.

Mental health care use in adolescents with and without mental disorders.

The aim of the study was to estimate the proportion of adolescents with and without a psychiatric diagnosis receiving specialist mental health care and investigate their problem levels as well as utilization of other types of mental health care to detect possible over- and undertreatment. Care utilization data were linked to psychiatric diagnostic data of 2230 adolescents participating in the TRAILS cohort study, who were assessed biannually starting at age 11. Psychiatric diagnoses were established at the fourth wave by the Composite International Diagnostic Interview. Self-, parent- and teacher-reported emotional and behavioral problems and self-reported mental health care use were assessed at all four waves. Of all diagnosed adolescents, 35.3 % received specialist mental health care. This rate increased to 54.5 % when three or more disorders were diagnosed. Almost a third (28.5 %) of specialist care users had no psychiatric diagnosis; teachers gave them relatively high ratings on attention and impulsivity subscales. Diagnosed adolescents without specialist mental health care also reported low rates of other care use. We found no indication of overtreatment. Half of the adolescents with three or more disorders do not receive specialist mental health care nor any other type of care, which might indicate unmet needs.

Lower dorsal striatum activation in association with neuroticism during the acceptance of unfair offers.

Unfair treatment may evoke more negative emotions in individuals scoring higher on neuroticism, thereby possibly impacting their decision-making in these situations. To investigate the neural basis of social decision-making in these individuals, we examined interpersonal reactions to unfairness in the Ultimatum Game (UG). We measured brain activation with fMRI in 120 participants selected based on their neuroticism score, while they made decisions to accept or reject proposals that were either fair or unfair. The anterior insula and anterior cingulate cortex were more activated during the processing of unfair offers, consistent with prior UG studies. Furthermore, we found more activation in parietal and temporal regions for the two most common decisions (fair accept and unfair reject), involving areas related to perceptual decision-making. Conversely, during the decision to accept unfair offers, individuals recruited more frontal regions previously associated with decision-making and the implementation of reappraisal in the UG. High compared to low neurotic individuals did not show differential activation patterns during the proposal of unfair offers; however, they did show lower activation in the right dorsal striatum (putamen) during the acceptance of unfair offers. This brain region has been involved in the formation of stimulus-action-reward associations and motivation/arousal. In conclusion, the findings suggest that both high and low neurotic individuals recruit brain regions signaling social norm violations in response to unfair offers. However, when it comes to decision-making, it seems that neural circuitry related to reward and motivation is altered in individuals scoring higher on neuroticism, when accepting an unfair offer.

Adolescent personality: associations with Basal, awakening, and stress-induced cortisol responses.

The purpose of the present study was to investigate the associations between personality facets and hypothalamic-pituitary-adrenal (HPA) axis functioning. Previous studies have mainly focussed on stress-induced HPA-axis activation. We hypothesized that other characteristics of HPA-axis functioning would have a stronger association with personality based on the neuroendocrine literature. Data (n = 343) were used from the TRacking Adolescents' Individual Lives Survey (TRAILS), a large prospective cohort study of Dutch adolescents. We studied the association between facets of Neuroticism, Extraversion, and Conscientiousness and basal cortisol, the cortisol awakening response (CAR), and four measures of stress-induced HPA-axis activity. Basal cortisol levels were related to facets of all three personality traits. The CAR and stress-induced cortisol were not related to personality. Possibly due to its more trait-like nature, basal cortisol seems more informative than stress-induced cortisol when investigating trait-like characteristics such as personality facets.

A longitudinal perspective on childhood adversities and onset risk of various psychiatric disorders.

It is well-known that childhood adversities can have long-term effects on mental health, but a lot remains to be learned about the risk they bring about for a first onset of various psychiatric disorders, and how this risk develops over time. In the present study, which was based on a Dutch longitudinal population survey of adolescents TRAILS (N = 1,584), we investigated whether and how childhood adversities, as assessed with three different measures, affected the risk of developing an incident depressive, anxiety, or disruptive behavior in childhood and adolescence. In addition, we tested gender differences in any of the effects under study. The results indicated that depressive, anxiety and disruptive behavior disorders each had their own, characteristic, pattern of associations with childhood adversities across childhood and adolescence, which was maintained after adjustment for comorbid disorders. For depressive disorders, the overall pattern suggested a high excess risk of incidence during childhood, which decreased during adolescence. Anxiety disorders were characterized by a moderately increased incident risk during childhood, which remained approximately stable over time. Disruptive behavior disorders took an intermediate position. Of the three childhood adversities tested, an overall rating of the stressfulness of the childhood appeared to predict onset of psychiatric disorders best. To conclude, the risk of developing a psychiatric disorder after exposure to adversities early in life depends on the nature of the adversities, the nature of the outcome, and the time that has passed since the adversities without disorder onset.

The neural correlates of worry in association with individual differences in neuroticism.

The tendency to worry is a facet of neuroticism that has been shown to mediate the relationship between neuroticism and symptoms of depression and anxiety. The aim of the current study was to investigate the neural correlates of state worry in association with neuroticism. One-hundred twenty participants were selected from an initially recruited sample of 240 women based on their neuroticism score. First, participants completed a questionnaire to assess the excessiveness and uncontrollability of pathological worry. Second, we measured brain activation with functional magnetic resonance imaging (fMRI) while participants were randomly presented with 12 worry-inducing sentences and 12 neutral sentences in a mood induction paradigm. Individuals scoring higher on neuroticism reported to worry more in daily life and to have generated more worry-related thoughts after the presentation of a worry-inducing sentence. Furthermore, imaging results showed the involvement of default mode and emotional brain areas during worry, previously associated with self-related processing and emotion regulation. Specifically, cortical midline structures and the anterior insula showed more activation during worry, when individuals indicated to have generated more worry-related thoughts. Activation in the retrosplenial and visual cortex was decreased in individuals scoring higher on neuroticism during worry, possibly suggesting reduced autobiographical specificity and visual mental imagery. In the literature, both these processes have been related to the cognitive avoidance of emotional distress. Excessive worry features in a number of emotional disorders and results from studies that elucidate its neural basis may help explain how and why neuroticism contributes to vulnerability for psychopathology.

Mismatch or cumulative stress: the pathway to depression is conditional on attention style.

In the study reported here, the main question we investigated was whether attention style could be a conditional adaptation. We organized participants of the TRacking Adolescents' Individual Lives Survey (TRAILS; N = 2,230) into shifters, sustainers, and two comparison groups, depending on their performance on a shifting- and a sustained-attention task at age 11 years. Compared with sustainers, shifters reported more pre- and perinatal risk factors and more childhood stress, and they adopted a faster life-history strategy. These differences were not found between the comparison groups, who performed well or poorly on both tasks, which suggests that specialization for either sustained or shifting attention is the key to conditional adaptation. In a subsample (n = 860), we found that stress did not increase depression risk in shifters, whereas a mismatch between early and recent stress predicted depression in sustainers. Cumulative stress predicted depression in the comparison group. These results suggest that shifters retain high levels of plasticity throughout life, whereas sustainers' adapted their phenotype early in life to the expected mature environment.